The field of the invention relates to new small molecules and uses of the new small molecules for modulating glucocerebrosidase activity. The new small molecules have a substituted quinazoline core structure and may be administered to treat diseases and disorders associated with aberrant glucocerebrosidase activity including neurodegenerative diseases, such as Gaucher's disease and Parkinson's disease
Glucocerebrosidase (EC 3.2.1.45), which also is called β-glucocerebrosidase, (β-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, or GCase, is an enzyme having glucosylceramidase activity. Glucocerebrosidase (GCase) is required to cleave the beta-glucosidic linkage of the chemical glucocerebroside, which is an intermediate in glycolipid metabolism. Glucocerebrosidase is localized in the lysosome and disabling mutations in the gene for glucocerebrosidase (GBA1) are associated with abnormal accumulation of lipids in lysosomes.
Genetic diseases caused by mutations in GBA1 include neurodegenerative diseases such as Gaucher's disease and Parkinson's disease. Gaucher's disease is a rare genetic disease caused by GBA1 gene mutations. Currently, the treatment for Type 1 Gaucher's disease is enzyme replacement therapy (ERT) administered every two weeks. ERT is very expensive and not effective for neuronopathic forms of Gaucher's disease. Mutations in GBA1 also are linked to Parkinson's disease (PD) and increase the risk of PD.
The so-called “pharmacological chaperone strategy” has been previously attempted in order to activate GCase as a treatment for diseases and disorders associated with deficient GCase activity. However, none of the compounds used in the pharmacological chaperone strategy were successful in activating GCase presumably because they targeted the active site of GCase.
Here, we disclose novel substituted quinazoline compounds which modulate glucocerebrosidase activity. Some of the novel compounds have potent inhibitory activity and binding affinity. As such, these compounds could be used as pharmacological chaperones. In addition, some of the compounds in the present study showed high activation activity in GCase activity assays and could be used as GCase activators. The novel substituted quinazoline compounds disclosed herein have better chemical and physical properties than previous reported non-active site GCase inhibitors. (See Marugan et al., J. Med. Chem. 2011; 54(4) 1033-58, the contents of which is incorporated herein by reference in its entirety). These better chemical and physical properties include polar surface area, solubility, increased number of rotatable bonds, and increased number of potential hydrogen bonding members.